J Immunol. 2026 Oct 1;215(10):vkag290. doi: 10.1093/jimmun/vkag290.
ABSTRACT
Age-associated B cells (ABCs) have emerged as critical components of adaptive immune responses linked to autoimmune disorders, aging-associated diseases, and chronic infections. Accumulation of ABCs is subjected to sex-specific regulation. A group of X-linked genes, including TLR7 and CXorf21/TASL, an adaptor that regulates IRF5 activity, are key regulators of ABCs. Because these genes can escape X chromosome inactivation (XCI) in immune cells, we investigated the contribution of biallelic expression of TLR7 and CXorf21/TASL, using RNA fluorescence in situ hybridization, in the TLR-driven development of ABCs and plasmablasts (PBs) in human B cells. Here we show that ABCs are more frequent in PBMCs from female of reproductive age as compared to age-matched males. Using a BCR/TLR/IFN-γ-driven ABC-differentiation model from naïve B cells, we show that ABCs, with dysregulated XCI at the TLR7 locus, are positively selected during TLR7-driven differentiation, but not in response to TLR9 stimulation. A similar trend was observed for CXorf21/TASL biallelic cells. We establish that IgD-CD27- (double-negative [DN]) B cells, that contain ABCs, were the immediate precursors of CD27hiIRF4+ PBs, in response to TLR stimulation. Interestingly, female B cells were more prone to generate PBs than male cells only in response to TLR7 stimulation compared to TLR9. This sex bias was associated with enhanced expression from both X chromosomes of TLR7 and, to a lesser extent, CXorf21 in TLR7-stimulated PBs. In conclusion, TLR7-induced ABCs and DN B-cell-derived PBs are associated with enhanced XCI escape of TLR7, suggesting positive selection of biallelic B cells upon cognate TLR engagement.
PMID:42961647 | DOI:10.1093/jimmun/vkag290